Aha Moments! When Researchers Find Inspiration in Unexpected Places
Dr. Alex Huang didn't expect to learn much when he casually poked his head into a meeting of colleagues researching adult cancer. After all, as a professor of pediatrics at Case Western Reserve University School of Medicine and program director at the Angie Fowler Adolescent & Young Adult Cancer Institute at University Hospitals Rainbow Babies & Children's Hospital in Cleveland, Dr. Huang's focus was on researching cancer in children. While adult and pediatric cancer research sometimes overlap, they often have very different priorities and trajectories.
As Dr. Huang listened to the discussion, however, something caught his attention. The researchers had been experimenting with a drug called Vactosertib, which was designed to inhibit the body's TGF-beta molecules to suppress tumor progression and metastatic growth. However, they weren't sure it was working because, unlike other medications they'd tried, this one didn't seem to have any side effects.
"The trial patients were taking this drug once or twice a day for five days, then they were off it for two days, and this weekly cycle repeats over periods of months," Huang explained. "And in that time, they didn't lose their hair. They didn't have any sores in their mouths. They didn't have any rashes on their skin. They didn't get diarrhea. Their blood cell counts didn't drop. Nothing."
This was in stark contrast to other TGF-beta inhibitors being utilized by adult and pediatric cancer researchers. Most drugs of that type had side effects, such as cardiac toxicity. Such side effects were minor enough in the short term that they could be safely used to treat adults. However, those same drugs posed a much greater risk for pediatric patients, whose potential longer lifespans meant they were more likely to experience negative long-term effects.
On a hunch, Dr. Huang took it upon himself to acquire some Vactosertib for his own research regarding possible treatments for osteosarcoma, a type of bone cancer diagnosed primarily in pediatric and adolescent patients. He then had his researchers give the drug to lab rats who had osteosarcoma tumors. The results took everyone by surprise.
"I wasn't holding my breath for any dramatic results, but, lo and behold, my researchers kept coming back to me and saying 'The tumors are shrinking after 3-4 weeks of being on this drug," Huang said. "The inhibitor reduced not only the size of the tumors, but also the spread of osteosarcoma cancer throughout the body."
Fast-forward to the present day and Dr. Huang, whose immunotherapy research has been supported by Pediatric Cancer Research Foundation grants, is set to embark on a massive, multi-continental, multi-institution Phase I/II clinical trial. The trial will take place in more than 20 hospitals throughout the United States, Europe, and South Korea. Meanwhile, MedPacto, the company that originally created the drug to treat adult cancers, has focused its Vactosertib strategy on targeting osteosarcoma.
None of this would have been possible if not for Dr. Huang's chance encounter with a group of people doing research that seemed, at first glance, completely unrelated to his own work. For Dr. Huang and countless other pediatric cancer researchers, "aha moments" like these are often few and far between, but that just underlines the importance of capitalizing on them when they do occur.
"The truth is, most aha moments happen when one least expects it. They can come at different times in different settings. There are examples where I'm just watching TV and, for no reason, I get these aha moments in my mind," Dr. Huang said.
"Most of the time, though, it comes from talking with folks, maintaining an open dialogue with students, researchers in the lab, collaborators, anyone who can bring in a different perspective. It may seem like what they're saying doesn't have anything to do with what you're working on, but if you're open to listening, you may be able to make that connection and say 'Wait a minute, I think there might be an answer here.'"
From Point A to Point Aha!
For Dr. Anat Erdreich-Epstein (Epstein), a pediatric oncologist and researcher specializing in pediatric brain cancers at Children's Hospital Los Angeles and Associate Professor of Pediatrics and Pathology at the Keck School of Medicine of USC, the journey from hypothesis to breakthrough isn't always a straight line from Point A to Point B. In fact, like for many researchers, it is more often a long, winding road full of unexpected twists and turns.
While some of those detours may be dead ends, other times, they can lead to eye-opening aha moments.
"You have to be open to the possibility that your hypothesis was incorrect," Dr. Epstein opined. "When you conduct an experiment and the results are "negative" and/or different from what you expected, your first instinct might be to just throw them away. But after you check thoroughly and conclude that the results were not because of technical error or an oversight (which are always possible in such complex experiments), then these different-than-expected results may be telling you something: that perhaps reality is different than the hypothesis you formulated. It is important not to discount such results, but to keep them in the back of your mind and go back to them from time to time, because sometimes they may be a clue to a very important finding."
One of Dr. Epstein's aha moments came when she was exploring if there was a link between a specific human gene she was studying at that time and outcomes of children with medulloblastoma, the most common malignant pediatric brain tumor. To help her, a colleague provided her with data he generated of genes whose level of mRNA expression in human medulloblastoma tumors correlated with survival of the children.
"The gene I was looking at was number 17 on that list in terms of correlation of its expression with how well patients did. That's very high on the list and may indicate very high correlation when you're talking about thousands of genes," Dr. Epstein said.
"Being curious as to what else was on that list, I didn't just look at that one gene. I also looked at the 16 genes that were before it, meaning that their level of expression was even more highly correlated with longer survival in children with medulloblastomas. The first gene on that list, which meant its expression in the medulloblastoma tumors was most highly correlated with survival of the patients the tumors came from, was PID1. I had absolutely no idea what the gene was and (like most others at the time) had never heard of it, which made me even more curious and prompted me to look into it.'"
Back then, PID1 was a "new" gene, having only been discovered a few years prior. As such, there were only two scientific papers published on it. One of them, published only months before she looked into what PID1 was, caught Dr. Epstein's eye. It suggested that PID1 functioned within a signaling pathway known to be linked to cancer, including to the brain tumors she had been researching.
At that time, there were only a few publicly available datasets that provided expression levels of genes in tumors and their correlation to patient survival times. Luckily, one of those datasets was of gliomas, another type of brain tumor. Doing this online analysis on PID1 showed that its level of expression was highly correlated with outcome of patients with gliomas: the lower PID1 expression, the shorter the patient's survival and vice versa. Finding such correlation in two different tumor types in two independent datasets justified looking a bit further, so Dr. Epstein began actively experimenting with PID1.
"I said, 'Let's put this gene into the cancer cells and see what it does to them.' Usually, with the methods we were using then, it would take about a month to accomplish this and be ready to start the analysis. After two months of waiting, when no one in the lab mentioned any results for this experiment yet, I asked, 'How are those cells with the PID1 transduction doing?' The response was, 'Well, it seems not to be working,'" Dr. Epstein recalled.
"When I asked for an explanation of 'what was not working', the response was 'the cells that received the control DNA are growing fine, but those into which we inserted the PID1 DNA are just not growing, so we can't do the experiments.' I then said, 'Think again about what it is that you are saying.' And that is when it clicked and the researcher said 'Aha, it actually is working!'"
Starting with that experiment that was "not working," Dr. Epstein's team realized that PID1 was capable of slowing the growth of certain types of brain cancers. In 2014, they published the first paper linking higher expression of tumor PID1 to longer survival in patients with medulloblastomas, gliomas, and in the dish, higher PID1 expression slowed growth of cells of these two brain cancers as well as a third: atypical teratoid rhabdoid tumor.
Since then, Dr. Epstein has continued investigating the relationship between PID1 and medulloblastomas and the molecular mechanism that regulates the anti-tumor effect, with support of grants from the Pediatric Cancer Research Foundation. These avenues of study are crucial in growing both our understanding of pediatric cancer and our ability to effectively treat it.
"Most of the time, you have a hypothesis and do an experiment to test that hypothesis: you may find that your results either fit the hypothesis or do not fit it. Everyone loves to get results that support their hypothesis. However, it is perfectly okay to find that the results do not fit the hypothesis," she said.
"In this case, as long as there were no technical problems/errors and all experimental controls were included, the conclusion is that the hypothesis was probably incorrect, at least in part, or inaccurate or not inclusive of some situations. The next step is to re-think the hypothesis to find one that is consistent with the results obtained, and then retest it, rather than discard the results and forget about them."
"A 'no' result to an experiment is just as valid and just as important an answer as a 'yes.' It is important because it tells you that the place where you are looking is not the right path and you have to go to a different path. That in itself can often be an aha moment."
Provided by California NanoSystems Institute